The Annapolis, Md., woman first suspected that an 87-year-old family friend was in deep trouble when he wrote, "How is your mother—still living in Florida?" The mother in question had been dead 15 years, and the family friend should have known it. Indeed, he was coming down with Alzheimer’s disease, it soon became obvious, and his memory deteriorated so badly that he confused Denny’s Restaurant in Annapolis with the U.S. Naval Academy.

But how about the 75-year-old woman who has misplaced her car keys and rummages around for them for an hour? Is she getting Alzheimer’s as well? And how about all those middle-aged people who panic when they forget a name or where their car is parked? Is it a "senior moment" or are they coming down with Alzheimer’s? When do memory faux pas indicate that a brain is being invaded by those sinister plaques and tangles that characterize the devastating, incurable disease called Alzheimer’s?

Although the line between normal memory difficulties and Alzheimer’s disease is thin indeed, researchers are coming up with ways to distinguish the temporarily memory-challenged from those truly getting Alzheimer’s. This was some of the most interesting news to emerge from the World Alzheimer Congress 2000, held in Washington, D.C. in July.

First, it is becoming apparent that brain changes can herald Alzheimer’s before outward symptoms of the disease occur. For instance, Nicholas Fox, M.D., of the Institute of Neurology in London, England, and his colleagues did serial MRI scans of the brains of persons at risk of familial Alzheimer’s as well as of the brains of a matched control group. The rate of loss in brain volume, they found, was greater in those at-risk persons who progressed to Alzheimer’s than it was in at-risk persons who did not, and also markedly greater than in the control group.

Along the same lines, a study by Gary Small, M.D., of the University of California at Los Angeles, revealed decreased blood flow to the brains of persons with a genetic risk of Alzheimer’s.

Changes in certain areas of the brain also seem to precede Alzheimer’s. Mony de Leon, Ed.D., of New York University School of Medicine and his colleagues used MRI and PET scans to measure the size of, and glucose metabolism in, three different brain areas of cognitively normal elderly subjects, persons with mild cognitive impairment (memory problems beyond what would be expected for their age), and patients with Alzheimer’s.

By comparing the brain scans of these three groups of subjects, they hoped to learn which brain changes might antedate and predict the transition from normal to mild cognitive impairment, and which brain alterations might occur before and predict the transition from mild cognitive impairment to Alzheimer’s.

The three brain areas they decided to focus on were the temporal lobe—important for the appreciation of sound and spoken language; the hippocampus—crucial for memory, and the entorhinal cortex, which nestles in front of the hippocampus and only during the past few years has been found to be vital for memory consolidation. As de Leon explained it in an interview, "Every piece of information that comes into the brain—olfactory sensation to vision to recollections of information which you’ve heard, any conscious material you are dealing with, perhaps even unconscious material—is coming through the entorhinal cortex."

And what de Leon and his colleagues found was intriguing. A reduction in both the size of the entorhinal cortex and in its metabolism appears to precede and predict mild cognitive impairment. A reduction in both the size of the hippocampus and in its metabolism seems to be present during mild cognitive impairment and pave the way for Alzheimer’s. And a reduction in the size and metabolism of the temporal lobe then seems to occur only after Alzheimer’s has set in, "although there are inklings of that in advance," de Leon admitted. "There are definitely, in some individuals, temporal lobe changes occurring during the mild cognitive impairment (MCI) stage. But it becomes extremely consistent at the time that Alzheimer’s is diagnosed."

So the general scenario suggested by these findings seems to be that as the Alzheimer’s disease process gets underway in the brain, the entorhinal cortex is the first to go, then the hippocampus, and finally the temporal lobe. Or if one viewed it as a horserace, the entorhinal cortex would win.

Also fascinating, the entorhinal cortex is located very close to the olfactory tract in the brain, and in Alzheimer’s the early involvement of the entorhinal cortex may be accompanied by early involvement of the olfactory tract. Stephanie Christen-Zaech of the University Institute of Pathology in Lausanne, Switzerland, and her coworkers have found a strong link between the presence of Alzheimer-type changes in the entorhinal cortex and Alzheimer-type changes in the olfactory tract.

These results indicate, she said, "that the involvement of the olfactory system is one of the earliest events in the degenerative process of the central nervous system in Alzheimer’s disease. Or as de Leon sees it, "It is really getting to the start of where Alzheimer’s begins."

The early involvement of olfactory nerves in Alzheimer’s, in fact, may explain why a loss in the sense of smell is one of the first outward symptoms of encroaching Alzheimer’s. Davangere Devanand, M.D., of Columbia University and his coworkers gave an olfaction test to 80 persons suspected of coming down with Alzheimer’s and to 40 controls. Of the 80 persons with suspected Alzheimer’s, 66 were followed up two years later. And of these 66 individuals, 18 were found to have developed Alzheimer’s, and their olfaction scores from two years previously showed that their ability to smell had been worse than had that of the 66 persons who had not converted to Alzheimer’s.What’s more, of the 18 who eventually came down with Alzheimer’s, those who had denied having a smell problem two years earlier turned out to be especially at risk of the disease, Devanand reported.

The major outward indication that a person is headed toward Alzheimer’s, of course, is memory problems, and it’s becoming a little more evident which type of memory problems are more likely to signal Alzheimer’s. David Bennett, M.D., of Rush-Presbyterian-St. Luke’s Medical Center in Chicago and colleagues studied 700 older nuns, priests, and brothers from 12 states over a seven-year period. All participants agreed to be evaluated psychologically on an annual basis until they died, then to be autopsied. Results of the study indicated that a decline in episodic memory was a good predictor of who would develop Alzheimer’s.

Along similar lines, Marilyn Albert, Ph.D., of Harvard Medical School and her coworkers conducted a study to determine whether certain neuropsychological factors are predictors of getting Alzheimer’s. In 1992 they recruited 146 subjects—114 with mild memory difficulties and 32 controls.They gave the subjects 17 neuropsychological tests at baseline and then followed them for three years to determine which persons would get Alzheimer’s.

Twenty-three of the 114 subjects with mild memory problems converted to a diagnosis of probable Alzheimer’s within a three-year period, Albert reported, and four of the 17 tests at the start of the study turned out to indicate who would eventually get Alzheimer’s. The four tests had to do with memory and executive planning.

In fact, if a person suffers memory problems on a regular basis, and this deficiency is confirmed by a family member, it could be that he or she is coming down with Alzheimer’s. Or as Ronald Petersen, M.D., Ph.D., of the Mayo Clinic explained to Psychiatric News, "We are all aging, none of us remembers quite as well as we formerly did. . . . But if someone else who knows you well comments, ‘You know, you have become more forgetful of things you used to remember,’ and most importantly, things that you want to remember, things that you try to remember, and you still can’t do it, that is a little more worrisome, I think, and merits an evaluation." And if the evaluation indicates mild cognitive impairment, it doesn’t bode well.

Petersen and his team followed 160 mildly cognitively impaired persons for six to 10 years; 80 percent of them eventually came down with Alzheimer’s. Kathleen Welsh-Bohmer, Ph.D., of Duke University Medical Center and coworkers studied elderly persons with memory impairments as well as normal older persons. The former declined more rapidly on neuropsychological tests during the subsequent four years than the latter did, with nearly 50 percent of the former progressing to Alzheimer’s.

Yet even if persons with ongoing memory problems have the odds stacked against them, all is not lost, since coming down with Alzheimer’s can take some time. The rate of conversion for the mildly cognitively impaired is 10 percent to 15 percent a year, versus 1 percent to 2 percent for mentally healthy persons of the same age, Petersen said. And there may be some who will never progress to full-blown Alzheimer’s, he conceded. "Nevertheless," he said, "the vast majority of people who experience a change in memory and meet the criteria for memory impairment probably have a pre-Alzheimer kind of condition."

Undoubtedly the most positive aspect of researchers being able to identify persons who are coming down with Alzheimer’s is that it enables them to try out drugs on these individuals that might help keep Alzheimer’s at bay.

In March 1999, for example, the National Institutes of Health launched a trial to see whether either donepezil (Aricept) or vitamin E might be able to slow or stop persons with mild cognitive impairment from getting Alzheimer’s.The study is being directed by Leon Thal, M.D., and Michael Grundman, M.D., of the University of California at San Diego, as well as by Petersen. At this point, Petersen told Psychiatric News, they’ve enrolled about 650 of the 720 subjects they want to recruit, and they will then follow them for three years.

Five clinical trials are now being conducted around the world to determine whether certain drugs might keep persons with ongoing memory difficulties from getting Alzheimer’s, Petersen pointed out at the World Alzheimer Congress 2000. When Alzheimer’s researchers come together for their next international meeting—in Stockholm, Sweden, in 2002—they should have some interesting and encouraging results to report from these trials, Petersen said.